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When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened.
Sequist's 37 re-biopsied patients showed that acquired resistance to EGFR inhibitors is a heterogeneous set of diagnoses: T790M, MET amplification, PIK3CA mutation, a change of cell state, and in 14 percent an outright transformation into small-cell lung cancer, which is sensitive to entirely different drugs. Three patients lost their resistance mechanism when the drug was withdrawn and responded again. Kobayashi's single patient in 2005 produced osimertinib.
Despite this, sequencing at progression is inconsistent: tissue re-biopsy is invasive and often declined, plasma testing is not reimbursed everywhere, and the result frequently arrives after the next line has started. The idea is to make a resistance profile, tissue where safe and plasma always, a required step before the next line, and to fund the pathway that makes it fast enough to act on.
The first regimen to beat osimertinib as first-line treatment for EGFR-mutant lung cancer. It sets up the choice that now faces every newly diagnosed patient: a more effective but harder combination now, or a simpler tablet with something held back for later.
Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right.
The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became.
Resistance to a targeted drug usually has a cause you can read off a sequence, which means it can be targeted in turn. Osimertinib exists because of this paper.
Shares Tracking the evolution of non-small-cell lung cancer, Next-generation sequencing (NGS), Tumour heterogeneity and clonal evolution, ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment and the tag lung-evidence.
Shares Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Diagnostics roadmap: stains → gene panels → blood tests that decide treatment, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares Tracking the evolution of non-small-cell lung cancer, Tumour heterogeneity and clonal evolution, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Lung cancer (all types) and the tag lung-evidence.
Shares Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Acquired resistance to every therapy, EGFR-mutated non-small-cell lung cancer and the tag lung-evidence.
Shares Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Lung cancer (all types) and the tag lung-evidence.
Shares EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, EGFR-mutated non-small-cell lung cancer and the tag lung-evidence.
Shares ALK-positive non-small-cell lung cancer, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Drug resistance (primary and acquired), Acquired resistance to every therapy and the tag lung-evidence.
Shares Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, EGFR-mutated non-small-cell lung cancer, Lung cancer (all types) and the tag lung-evidence.